Aztreonam Aerosol to Treat Cystic Fibrosis Nasal Disease

This study is designed as a masked, two center, randomized, placebo-controlled pilot study to evaluate the safety and efficacy of nasal and oral inhalation of 75 mg aztreonam in subjects with CF and lung infection due to PA. The study will involve two sites: Virginia Commonwealth University Medical Center (VCU) and Eastern Virginia Medical School (EVMS). Potential subjects will be identified in each site's CF clinic.

Study Overview

• Status: Terminated
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Oral Aztreonam; Drug: Nasal Placebo; Drug: Nasal Aztreonam

Detailed Description

This study is designed to explore the efficacy and safety of nasal aztreonam administered using the Pari Sinus Nebulizer combined with oral Cayston aerosol therapy compared to placebo on clinical and laboratory endpoints such as risk of antibiotic-resistant Pseudomonas aeruginosa (PA), time to pulmonary infection exacerbation, nasal quality of life, pulmonary function, nasal and lower airway cultures, and properties of mucus.

P. aeruginosa (PA) is a primary cause of lung infections in persons with cystic fibrosis (CF) (1). Over the past decade, studies have shown that aerosolized antibiotics can reduce lower respiratory bacterial load, decrease exacerbations of pulmonary disease, and in many patients improve pulmonary function. Cayston (aztreonam) oral aerosol using the PARI Altera Nebulizer System was approved by the FDA in February 2010 for CF patients 7 years of age or older with PA (2). In 2011, 35.8% or patients in the National CF Patient Registry used Cayston for treatment (3). Bacterial cultures suggest that the upper airways and lower airways of CF patients are cross-infected by PA and that the paranasal sinuses can act as a bacterial reservoir (4). There is improved post-transplanation patient survival for recipients that undergo sinus surgery and daily nasal washes to reduce bacterial load (2).

Routine CF care does not generally include upper airway assessment. There are no published studies evaluating the effect of aerosol antibiotics to treat nasal and sinus infections in CF in combination with oral inhaled aerosol therapy to treat the lower airway disease. However Mainz and colleagues published a case report that suggested that sinonasal administration of tobramycin using the Pari Sinus nebulizer (Pari Corp, Starnberg, Germany) delayed PA lower respiratory infection in a 12 year-old with CF who had chronic mucopurulent rhinosinusitis (5) and studies in chronic obstructive pulmonary disease suggest that treating upper airways can also improve coexistent lower airway disease.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Children's Hospital of Richmond at VCU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 100 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or females 7 years of age or older and able to perform pulmonary function testing
2. Confirmed diagnosis of CF by the 1997 CF Consensus Conference criteria and followed by the VCU or EVMS CF clinic
3. Presence of PA in 2 lower respiratory tract (sputum) cultures in the 24 months before screening
4. Subjects and/or parent guardian must be able to give written informed consent prior to any study related procedure
5. All sexually active female subjects who are of childbearing potential must agree to use an effective method of contraception (i.e.condoms or abstinence).
6. All sexually active female subjects must have a negative pregnancy test at screening (V0).
7. Clinically stable determined by the study physician with no significant new respiratory symptoms.
8. Presence of PA in nasal culture (swab or secretion) or sinus culture obtained in the 12 months before screening or at screening visit

Exclusion Criteria:

1. Use of oral, IV or inhaled antibiotics within 0 days before study other than low dose azithromycin
2. Severe pulmonary disease with FEV1<30% predicted of baseline SpO2<0.90
3. ENT surgery within 6 months of screening
4. Allergy or documented adverse reaction to aztreonam
5. Epistaxis or significant (>30mL) hemoptysis in the past 6 months
6. Frequent (weekly or more frequently) or severe headaches
7. Subject is unlikely to comply with the procedures scheduled in the protocol
8. Subject participates in another clinical trial within 30 days prior to study entry
9. Subjects who have had a lung transplant will be excluded
10. Prisoners will be excluded
11. Non-English Speaking patients will be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Therapy; Oral Inhalation via PARI Altera Device: Standard Therapy Comparator (Oral Aztreonam 75mg three times a day) AND Nasal Inhalation via PARI PAS Device: Nasal Placebo-Normal Saline twice per day	Drug: Oral Aztreonam; Standard Therapy Comparator (Oral Cayston 75mg three times a day); Other Names: Cayston; Azactam; Drug: Nasal Placebo; Placebo (nasal saline twice per day); Other Names: Saline
Experimental: Study Therapy; Oral Inhalation via PARI Altera Device: Standard Therapy Comparator (Oral Aztreonam 75mg three times a day) AND Nasal Inhalation via PARI PAS Device: Experimental- Nasal Aztreonam 75 mg twice per day	Drug: Oral Aztreonam; Standard Therapy Comparator (Oral Cayston 75mg three times a day); Other Names: Cayston; Azactam; Drug: Nasal Aztreonam; Study Therapy (nasal Aztreonam 75mg twice per day); Other Names: Cayston; Azactam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Protocol-defined Pulmonary Exacerbations Treated With IV Anti-pseudomonal Antibiotics on Day 140	Protocol-Defined Pulmonary Exacerbation includes events that are characterized by change or worsening pulmonary symptoms (increased cough, increased sputum production and chest congestion, decreased appetite and exercise tolerance), loss of weight, and lung function decline that prompt initation of antibiotic therapy. Protocol-defined exacerbations in subjects that warrant treatment with IV antibiotics will be determined from the medical record during the course of this study.	140 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Protocol-defined Pulmonary Exacerbation Treated With IV Anti-pseudomonal Antibiotics	Protocol-Defined Pulmonary Exacerbation includes events that are characterized by change or worsening pulmonary symptoms (increased cough, increased sputum production and chest congestion, decreased appetite and exercise tolerance), loss of weight, and lung function decline that prompt initation of antibiotic therapy. Protocol-defined exacerbations in subjects that warrant treatment with IV antibiotics will be determined from the medical record during the course of this study. The time of beginning the study to first protocol-defined pulmonary exacerbation will also be determined from the medical record during the course of this study.	Up to 6 months
Change in Sinus and Nasal QoL Questionnaire (SNOT-20) on Day 140 and Day 168	The Sino-Nasal Outcome Test 20 (SNOT-20) is a validated health-related QOL questionnarie designed to determine the impact of sinonasal dysfunction. Patients will assess nasal symptoms, emotion, and activity on a scale of worsening symptoms scored 1 through 7 to provide a quantifiable score capable of disease severity. It has been shown as a responsive measure of health-related quality of life and suitable for use in outcomes studies and routine clinical care. Survey responses from Day 140 and Day 168 will be compared to the SNOT20 survey responses from previous visits (V1, V2, and V4)	Day 140 and Day 168
Change in Cystic Fibrosis QoL Score (CFQ-R) on Day 140	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The CFQ-R was administered at Visits 1, 6, and 7. The endpoint was change in CFQR on day 140 compared to V1 and V5.	Day 140
Change in Pulmonary Function (FVC and FEV1 Percent Predicted) on Day 140	Routine spirometry will be performed according to American Thoracic Society (ATS) guidelines. A minimum of three maneuvers will be performed. The largest FVC and FEV1 will be reported after examining data from all acceptable curves even if they did not originate from the same maneuver. Data will be expressed both in absolute values and as percent (%) predicted based upon NHANES predicted values.	Day 140
Change in Paired Sputum Cultures and Nasal Swabs for Bacteria and Antibiotic Resistance	Expectorated sputum and nasal swabs will be cultured at each visit using standardized procedures to identify CF pathogens as well as susceptibility to a standard panel of antibiotics.	1 year
Change in Acoustic Rhinometry for Nasal Obstruction (Volume) (Will be Measured at VCU Site ).	Acoustic rhinometry is used to measure cross-sectional volume of the nasal cavity allowing the calculation of nasal volume. Reflected sound waves are painlessly introduced through nasal adaptors into the nasal passages allowing the production of area-distance graphs.	1 year
Number of Safety and Adverse Events Including Nasal Stuffiness, Epistaxis, and Headache.	The frequency, severity and duration of all nasal and pulmonary adverse events, regardless of cause, will be recorded in REDCap as an electronic case report form. Serious adverse events will be captured in OnCore. The frequency and severity of adverse events will be calculated for each patient, with each patient counted once using the most severe grade experienced. The duration of adverse events will be calculated by the number of days each event persisted. Tables will be generated for all adverse events including serious adverse events and withdraws from the study.	1 year
Number of Protocol-defined Pulmonary Exacerbations Treated With Oral Anti-pseudomonal Antibiotics	Protocol-Defined Pulmonary Exacerbation includes events that are characterized by change or worsening pulmonary symptoms (increased cough, increased sputum production and chest congestion, decreased appetite and exercise tolerance), loss of weight, and lung function decline that prompt initation of antibiotic therapy. Protocol-defined exacerbations in subjects that warrant treatment with oral antibiotics will be determined from the medical record during the course of this study.	1 year

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Collaborators: Eastern Virginia Medical School
• Investigators: Principal Investigator: Bruce K Rubin, MD, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): September 19, 2019
• Study Completion (Actual): September 19, 2019

Study Registration Dates

• First Submitted: November 3, 2015
• First Submitted That Met QC Criteria: March 31, 2016
• First Posted (Estimate): April 6, 2016

Study Record Updates

• Last Update Posted (Actual): January 28, 2021
• Last Update Submitted That Met QC Criteria: January 11, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; P. aeruginosa (PA)
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Otorhinolaryngologic Diseases; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Nose Diseases; Anti-Infective Agents; Anti-Bacterial Agents; Aztreonam
• Other Study ID Numbers: HM20005657

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Individual participant data will be deidentified and will not be availalble.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No